The use of sulfonylureas in treating type 2 diabetes is fully established as an effective means of controlling hypoglycemia. At the molecular level, sulfonylureas act on the receptor in β pancreatic cells known as SUR, which, when it is activated, closes an ATP dependent potassium channel, which in turn causes a reduction in potassium intake and in consequence depolarization of the membrane. This in turn causes an increase in the flow of calcium toward the cell's interior, activating the cytoskeleton, which causes translocation of secretory granules, thereby releasing insulin by exocytosis.
Another treatment whose use has spread recently is with the biguanide metformin, which acts effectively not only to control hypoglycemia, but also in its prevention. Metformin has a different mechanism of action from sulfonylureas, increasing insulin sensitivity in hepatic and peripheral tissue (mainly muscular tissues). Metformin inhibits gluconeogenesis and hepatic glycogenolysis. At the cellular level, heightened insulin sensitivity is explained by the increased activity it induces in the tyrosin kinase post-receptor and the resulting increase in the number and activity of GLUT4 transporters.
However, around 75% of type 2 diabetes patients treated with sulfonylureas do not succeed in bringing their glucose level to the desired values, and need to complement their treatment with a second oral agent. Also, most patients with single drug treatment using sulfonylureas after a certain number of years require an additional drug that contributes to their control therapy in order to achieve a suitable level of glycemic control. This loss of effectiveness is attributed to various causes, which are not yet well established, such as the supposition that gradual deterioration of the pancreas renders it unable to maintain an exacerbated insulin excretion rate for a long period of time due to constant, long-term stimulation caused by sulfonylurea therapy. However, contrary to this explanation, metformin therapy, which does not act by over stimulating β cells, also presents lack of response after prolonged use, which would be contradictory to the explanation given for the lack of response of sulfonylureas.
On the other hand it has been found that combining sulfonylurea and metformin therapy is more effective than monotherapy with either of the two medications. Thus, it has been fully proven that the hypoglycemic action of metformin is completely additional to that of sulfonylureas (de Fronzo, R. A. and Goodman, A. M. Yn, England J. Med. 333:541 (1995)).
Its also has been reported that when monotherapy with sulfonylureas does not achieve the desired levels it should not be discontinued and replaced by metformin monotherapy, as this will not lower glucose levels in plasma below the values observed with sulfonylurea monotherapy (Rosenstock, J. et al., Diabetes Care 19:1994 (1996); (Gasber, A. J., et al., Amer. J. Med. 103:491 (1997)).
It is generally recognized that, because diabetes mellitus is a progressive disease, patients with good initial response to oral agents will eventually require a second medication to achieve the desired glycemic control. As we have mentioned, adding metformin to sulfonylurea therapy or vice-versa produces an additive response, not only to the reduction in glucose, but also to the reduction in lipids (Hermann, L. S., et al., Diabetes Care, 17:1100 (1994)).
There are several reports on the combined use of the sulfonylurea glibenclamide with the biguanide metformin. See, e.g., WO 97/17975; Vigneri et al., Diabetes and Metabolism, 17:232-234 (1991); Higginbotham et al., Med. J. Austr., 154-156 (1979); U.S. Pat. No. 6,303,146; and WO 01/32,158.
Furthermore, there are several references on the combined use of the sulfonylurea glipizide with metformin. See, e.g., Cefalu et al., Diabetes, 45 (Supl. 2):201A (1996); Croase et al., Circulation, 94 Supl 1508 (1996); and Cefalu et al., Diabetology, 39 (Supl. 1): A231 (1996).
It has been reported that there are no great differences in efficacy among various sulfonylureas (R. A. De Fronzo, Annals of Internal Medicine, 131:281-303 (1999)); S. Dagogo-Jack, et al., Archives Internal Medicine, 157:1802-1817 (1997); A. J. Scheen et al., Drugs 55:225-236 (1998); R. Bressler et al., Archives Internal Medicine, 157:836-848 (1997). Other reports indicate that glimepiride shows a potency two times higher than that of glibenclamide (R. Groomis et al., Endocrinology, 13:117-121 (2000)). Moreover, in contrast to glibenclamide, chronic treatment of type 2 diabetic patients with glimepiride will not impair the vasodilator function of KATP opening in vivo (E. J. Abbink et al., Diabetic Medicine, 19:136-143 (2002). Furthermore, a lower incidence of severe hypoglycemia was reported in type 2 diabetic patients treated with glimepiride versus glibenclamide (A. Holstein et al. Diabetologia, 157:A40 (2000). Finally, Kramer et al., Biochimica et Biphysica Acta 1191:276-290 (1999)), reported that glimepiride acts on a different receptor site on the β-cell than does glibenclamide, and that glimepiride interacts with the β-cell receptor for less time. Unlike glibenclamide, glimepiride seems to work in part by enhancing both the sensitivity and reponsiveness of peripheral tissue to insuline (J. Sato et al. Excerpta Medica, 341-348 (1994), G. E. Sonnenberg et al., Annales Pharmaceuticals, 31:671-676 (1997)).